Abstract

Apicomplexans are a phylum of intracellular protozoan parasites that impose major medical and economic burdens on human societies the world over. They include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). The evolution of parasite resistance to frontline drugs, coupled with issues around drug toxicity and low drug efficacy against dormant parasite stages, means that new drugs to treat apicomplexan infections are much needed. Most apicomplexans contain a mitochondrion that is critical for their survival and pathogenesis. The mitochondrion of apicomplexans contain numerous differences from the mitochondrion of the animals these parasites infect, and we have explored its role in parasite biology and as a potential drug target. We have undertaken genome-wide, CRISPR-based forward genetic screens in Toxoplasma parasites lacking enzymes that contribute to key aspects of mitochondrial metabolism. These studies have revealed numerous functional redundancies and dependencies between mitochondrial metabolism and other metabolic pathways in the parasite. We are exploring whether this metabolic flexibility contributes to the extraordinary host cell range of these parasites. We have also developed medium throughput assays for measuring mitochondrial electron transport chain (ETC) activity, and used these to screen compound libraries for candidate ETC inhibitors. These screens have identified potent inhibitors of the ETC of both Toxoplasma and Plasmodium parasites, and which remain active in drug resistant parasites. Taken together, our data elucidate multiple roles for the mitochondrion in parasite biology, and we have exploited its essentiality to identify novel inhibitors that could be developed for treating parasitic infections.

Speaker Biography

A/Prof Giel van Dooren

Giel van Dooren is a lab leader in the Research School of Biology at the Australian National University. He undertook his PhD research in the School of Botany at the University of Melbourne (2001-2005), examining organellar biology of the malaria-causing parasite Plasmodium falciparum. He was awarded an NHMRC CJ Martin Overseas fellowship, which he undertook at the University of Georgia, USA (2005-2009), switching parasites to study Toxoplasma gondii, the causative agent of toxoplasmosis. He was awarded an ARC QEII Fellowship in 2011, and moved to the Research School of Biology at the Australian National University in 2012. Here his group focuses on how intracellular parasites like Toxoplasma and Plasmodium acquire nutrients from their host, and how they metabolise these nutrients in order to proliferate and cause disease. This includes examining unique features of the mitochondrion of these parasites, and identifying new drugs that target parasite mitochondrial biology.